Fatty acids delivered to tissues may be derived from three sources: 1) fatty acids generated by hydrolysis of lipoprotein triglyceride by endothelial bound lipoprotein lipase (LpL), 2) fatty acids circulating associated with albumin, 3) fatty acids that are a component of unhydrolyzed triglyceride in lipoproteins. This proposal will focus on how fatty acids are normally accumulated by the heart and how excess fat leads to cardiac dysfunction. This is analogous to the cardiac dysfunction that is seen in models of obesity that have lipotoxic cardiomyopathy. The two specific aims will assess lipid uptake and cardiac function in hearts that have reduced triglyceride lipolysis or increased LpL associated with cardiomyocytes. Aim 1 will determine the role of localized lipolysis in cardiac uptake of fatty acids. LpL will be inhibited or dissociated from its endothelial binding site, or genetically altered mice that have are defective in cardiomyocyte expression of LpL will be studied. Our Preliminary Results suggest that LpL is central to cardiac uptake of TG and its loss is likely to alter the metabolism of other caloric sources. Using newly created Floxed LpL mice we will specifically eliminate LpL from the cardiomycyte and assess the effect of chronic loss of lipolysis on heart energetics. Aim 2 includes experiments to study whether LpL that is unable to dissociate from the cells and transfer to the endothelial surface mediates tissue lipid. To do this, we will study lipid uptake in transgenic mice that express GPI-anchored LpL in cardiomyocytes. Our Preliminary Results show that these mice develop a cardiomypathy and excess lipid accumulation and have premature death. The defect in heart function will be studied in detail and methods to correct it using genetic crosses, diets and drugs are proposed. Both aims include experiments to study cardiac function, substrate oxidation, and gene expression. Our overall objective is to understand how the heart derived energy from fat, how it compensates for a defect in fat uptake, and how excess fat leads to cardiac dysfunction and premature death.